Despite medical advances, multiple myeloma remains a fatal disease underscoring the urgent need for better therapies. Multiple myeloma progression is dependent on interactions with normal cells of the bone microenvironment including osteoblasts and osteoclasts. These interactions lead to extensive bone destruction that greatly impact the patient's quality of life. We have shown that matrix metalloproteinases (MMPs) such as MMP-2 are key mediators of tumor-bone interaction via the regulation of cytokine and growth factor bioavailability and bioactivity. In humans, studies have identified that MMP-2 expression is present in late stage disease while our preliminary analyses of clinical specimens have demonstrated that MMP-2 is highly expressed in the myeloma and host compartments. Importantly, MMP effects are known to be context and tissue dependent and to date, no studies have examined whether cancer or host derived MMP-2 contribute to the progression of Multiple Myeloma. Using an innovative approach of generating selective MMP-2 inhibitors built on a bisphosphonic backbone in order to specifically target the skeletal tissue, hence the cancer-bone microenvironment, emerging studies indicate that our bone seeking MMP-2 inhibitors (BMMPIs) are efficacious in preventing myeloma progression in vivo compared to bisphosphonates alone. These observations further implicate a role for MMP-2 in promoting multiple myeloma growth. Critically, our novel BMMPI compounds allow for the circumvention of issues such as dose limiting side effects noted in previous clinical trials in which broad-spectrum MMPs were systemically delivered. Taken together, our preliminary findings provide rationale for the hypothesis that MMP-2 contributes to multiple myeloma progression and that the selective targeting of MMP-2 with BMMPIs will be therapeutically effective for the treatment of multiple myeloma. We will test our hypothesis by 1) defining the role of tumor and host derived MMP-2 in multiple myeloma progression using genetic approaches and; 2) fully evaluating the impact of MMP-2 selective BMMPIs as a single therapeutic agent on the progression of multiple myeloma. Pilot pharmacokinetic and pharmacodynamics (PK/PD) studies with the lead BMMPI will also be performed. Based on the anticipated results, we expect that interrogating the role of tumor and host derived MMP-2 in multiple myeloma will reveal a number of novel insights as to how the disease progresses in the bone microenvironment. Excitingly, our results will also shed light on the efficacy of a novel skeletal targeting MMP-2 inhibitor agent for the treatment and eradication of multiple myeloma. Furthermore, given that bisphosphonates are well tolerated by patients, we predict that the lead BMMPI candidate could be rapidly translated to the clinical setting.